The 2013 Nobel Prize in Chemistry: Karplus, Levitt and Warshel

The 2013 Nobel Prize in Chemistry goes to Martin Karplus, Michael Levitt and Arieh Warshel for applying both quantum and classical physics to develop computer models of chemical systems that show details of chemical reactions

Steve Mirsky: Welcome to this third episode of our special Nobel Prize editions of Science Talk, the podcast of Scientific American. I’m Steve Mursky.

Staffan Normark: This year’s prize is about taking the chemical experiment to cyberspace.

Steve Mirsky: Staffan Normark, Permanent Secretary of the Royal Swedish Academy of Sciences at a press conference in Stockholm that took place at 5:45 a.m. U.S. Eastern Time, this morning.

Staffan Normark: The Royal Swedish Academy of Sciences has decided to award the 2013 Nobel Prize in Chemistry to Professor Martin Karplus at Universite de Strasbourg, France, and Harvard University, Cambridge, Massachusetts, USA; and Professor Michael Levitt at Stanford University School of Medicine, California, USA; and Professor Arieh Warshel at University of Southern California, Los Angeles, USA.

And the academy citation runs for the development of multiscale models for complex chemical systems.

Steve Mirsky: Sven Lidin, the Chair of this year’s Nobel Committee for Chemistry then gave a short summary.

Sven Lidin: Chemistry is an experimental science but today theoretical chemists are providing answers to questions concerning complex chemical reactions. Theoretical chemists are working together with experimentalists to help us understand the complex reactions in photosynthesis, how to design drugs to fit with their target molecules in the body, and how a catalyst works in your car or in chemical industry to model chemical reactions. You can use two completely different sites of physics and chemistry. That is the world of quantum physics and the world of classical physics.

Quantum physics allows us to look at chemical reactions in exquisite detail but it is a method that demands a lot in terms of computer power and for large complex systems it is beyond what is possible today and will remain impossible to reach even for the foreseeable future.

Classical Newtonian physics on the other hand is relatively easy to handle and can be used for very, very large systems indeed but these models have the drawback that they cannot model the making and breaking of chemical bonds, chemical reactions. The natural way to use the two is together and so what is needed is a way to find quantum mechanics and classical mechanics to shake hands.

Now actually handshaking isn’t all that simple and the contributions from this year’s laureates, Professor Martin Karplus, Professor Michael Levitt and Professor Arieh Warshel is that they have provided that secret handshake that brings theoretical chemistry together as one unit.

Staffan Normark: Thank you, Professor Lidin, and now Professor Gunnar Karlstrom, are you ready to give a more detailed presentation?

Gunnar Karlstrom: Well I don’t know if anything more needs to be said but I’ll try to do something anyway. This year’s Nobel Prize laureates, they have done something extraordinary. They have actually made theory an equal partner to experiment.

For me as a theoretician this was unthinkable 20 years ago or so. We were always inferior to the experimentalists. They always knew what was right and we were always saying – we tried to stay with it but now today theory is actually an equal partner and why has that happened?

Well the reason is that today’s chemistry is focused a lot on function and reactions, and these are issues which are hard for experimentalists to assess. Basically molecules are lazy creatures that – most of the time they don’t do anything. They’re just sitting around and doesn’t do anything and then suddenly when they react everything goes quick like that and that’s very hard to study experimentally because you look at it and nothing happens and then suddenly everything happens.

Theory doesn’t suffer from this. Theory controls time, theory controls everything so we can make things do exactly what we want and in that way theory is an excellent complement to experiment and normally the experimentalist provides the structure to the theoretician and the theoretician, he analyzes the structure and he suggests reactions, mechanisms, so on; gives them back to the experimentalist who verifies or falsifies and gives back suggestions about new calculations that should be done, and together, they climb the never-ending stairs of chemical knowledge.

So what can we do with this type of modeling? Photosynthesis is something which is interesting to everybody. Can we solve the problem of photosynthesis? We have an infinite amount of energy available to us or new pharmaceuticals, the docking of a protein with a drug is an extremely important phenomenon; can we solve these problems in the computer, then we don’t need to do any experiments on rats maybe, at least can do fewer.

The problem is quantum chemistry works with wave functions. Wave functions doesn’t allow it to calculate position and velocity; position and speed at the same time, because that’s the way quantum mechanics is. So you can’t really make them work together, not easily, but this year’s Nobel Prize laureates realized that if you treat some degrees of freedom using quantum mechanics and some degrees of freedom using classical mechanics then it may work if you provide a suitable coupling between the classical and quantum degrees of freedom.

The advantage of this is that you reduce the number of particles and when you reduce the number of particles simulations modeling is quicker. So it’s all about making the calculations with the minimum needed effort but getting the maximum possible accuracy and this – for some type of application this is a very good model.

So what do we gain from this? We gain understanding. Understanding is something which cannot easily be provided by experiment but from the calculations that we do we can say why is this reaction proceeding, what is the reason for the reaction barrier, can we live with the barrier by some technique maybe, has it an electrostatic origin, does it require a lot of energy to bring direct and – I mean direct – to react molecules together maybe?

Okay, then maybe we could put something which facilitates that, some charged particle which facilitates that. So the immense success of this basically is that it gives us understanding and with that I think I should stop here and hopefully we have some of the laureates on the line.

Staffan Normark: We have Professor Warshel here with us on the phone. It’s very early, 3:00 or so in Los Angeles. Are you there, Professor Warshel?

Arieh Warshel: Yes.

Staffan Normark: How do you feel at this very early morning time for you?

Arieh Warshel: Extremely well.

Staffan Normark: That’s good to hear. I’m sitting here in the session hall of the Royal Swedish Academy of Sciences and in front of me are --

Arieh Warshel: I see you.

Staffan Normark: Oh, you see us as well? Well we have a lot of persons from the media all over the world and are you willing to take some questions from them?

Arieh Warshel: Very glad to.

Staffan Normark: Do we have a question?

Arieh Warshel: Yes.

Staffan Normark: Please start there.

Question: Yes, hello Professor Warshel, my name is Maria Gunther Axelsson. I am writing for Swedish daily newspaper, Dagens Nyheter and we just had a presentation here on what you have done and could you just say something that have been easier to understand now that you couldn’t understand before you had this?

Arieh Warshel: Usually I say it in a more complex way but what we’ve done from what I was able to see from the presentation of Gunnar is to develop methods that allow how things actually work because x-ray structure have been exist for some time and it’s like seeing the watch and wondering how actually it works.

So in short what we develop is a way which require a computer to look, to take the structure of a protein and then to eventually understand how exactly it does what it does, like if you have an enzymes that digest food and the structure exists you want to understand how this is happening and then you could use it for example to design drugs or just, like in my case, to satisfy your curiosity.

Question: Hello, my name is Joanna Ross.

Arieh Warshel: Hello.

Question: I am writing for a Swedish popular science magazine, Forske Ramsteg. Congratulations for the prize. I am curious about what is the work that you are doing now.

Arieh Warshel: On one hand I continue to use this combined quantum molecular mechanics to understand how are things that are responsible to transfer signals in the cells, how they exactly work, so this is like 30 percent of what I am doing and I also use this simpler representation to understand how molecules – how molecular models work; to understand how very complex molecules are working.

So it’s – all the time it’s how these things are working and every time it’s for a more complex question.

Staffan Normark: Thank you, once again, Professor Warshel and congratulations. We are looking forward all to see you here in Stockholm in December for the Nobel Prize Ceremony.

Arieh Warshel: Thank you very much in looking forward.

Steve Mirsky: Sven Lidin then spoke with Swedish Science Journalist, Joanna Ross. Sven Lidin, you mentioned that nowadays the chemistry is in the cyberspace. I thought it’s far away. I thought that chemistry is just in laboratories.

Sven Lidin: Well of course, chemistry is an experimental science but what has happened over the past few years, it’s really a fascinating development. When I was a young chemist theoreticians would come to us with ideas about how a system behaved and if they – if their predictions would scan with our experiments they would be happy.

If the two did not agree we were always sure that the theoreticians were wrong again. Today when theoreticians come with a prediction that we cannot prove is correct or disprove, well, normally we as experimentalists go back and check our experiments again because it may just as likely be we who are in the wrong today.

This is how far theoretical chemistry has come to become one of the tools, I would say, of experimental science because the sort of theoretical chemistry that this year’s laureates have been laying the foundation for are simulations.

They’re really numerical experiments that tell us a lot about how chemical systems work. So I would say to us theory has become the new experiments.

Joanna Ross: What happened then? What made the theory to be in this role now?

Sven Lidin: Definitely the contribution of this year’s laureates is central to that because what they have done is marrying the two worlds of quantum physics and classical physics. Quantum physics will really provide us with all the answers that we could possibly look for. Quantum physics has the wonderful ability to stop time and to expand space so that we can look at the tiniest detail of a system and we can look at this during any fraction of time that we choose.

The problem is that the demands on computer power are immense and it’s completely impractical to use this for any system of size. Therefore we have to use classical physics to describe the bulk of a system and it turned out that to marry these two is no simple matter. It really took a large concerted effort over a number of years to show that it was even possible which is, of course, what the laureates did.

Joanna Ross: Quantum physics is a lot about probabilities and statistics. Is this a difficulty?

Sven Lidin: Yes, quantum physics is one way of parameterizing the world. Classical mechanics is a completely different way of giving a model for basically the same system. Now one thing is that you can make the two and compare them and that works beautifully.

The problem is to take one part of a system and describe it in terms of quantum physics, and another part of the system and describe it in terms of classical physics.

You then have to find the correct boundaries to put between the two systems and to use the input from the classical mechanics as boundary conditions for the quantum mechanics and vice-versa.

And this means that we can look at systems of -- I shouldn’t say any size -- but we can look at vastly more larger systems and more complicated systems, and this is of course what we need in order to understand the systems that chemists are studying today; huge supermolecular systems, biochemical molecules, large assemblies in material science, and all these disciplines use the theory that was – that was founded by our three laureates.

It is really a cross-disciplinary part of chemistry which goes into all the fields and enriches them.

Joanna Ross: Does it mean that if you don’t have the theoretical model you don’t really understand what’s going on?

Sven Lidin: It’s always a question of complexity. If you have a simple system you can get very dependable answers by using just experiment but experiment and theory go hand in hand. We need to understand why things happen, we need to understand what makes things happen and as Gunnar Karlstrom was explaining during his resume of the prize the real problem is that most chemical methods tell us about what things looked like before a reaction and what they look like after reaction.

There is a classical picture of this which is given in many textbooks of chemistry where a chemical reaction is likened to a piece of drama and if you go in and make the measurements before and after it’s like seeing the actors before Hamlet and all the dead bodies after and then you wonder what happened in the middle, and actually there is some interesting action there and this is what theoretical chemistry provides us with, the whole dram.

Joanna Ross: Yeah, so you want to be in the eye of the storm, so to say?

Sven Lidin: Absolutely.

Joanna Ross: I understand but what are the possible applications of that? What are the benefits besides inside science?

Sven Lidin: I would say they’re not possible. They are there already today. There is not a pharmaceutical company that doesn’t have a theory division that works on trying to predict how a molecule will interact with the targets in the body.

This means that all development of new pharmaceuticals has a background in theory. When you are looking at devising new chemical reactions, when you are trying to create a new hard material or a new material with specific properties, if you want to optimize the electronic properties of material , the magnetic properties of material, you always start out with theory because it saves you so much time in the lab.

Now theory is not perfect. You still have to do the experiment but the predictions that theory make are becoming so much more powerful these days that we can perhaps save 90 percent of the experimenting and concentrate on the 10 percent where we know that the most important results, we like.

So we save a lot of money, we save a lot of time and we save a lot of effort by doing the theoretical homework first. It’s like in the old days when everyone told you you have to read the literature now everyone will tell you you have to make the calculations.

Joanna Ross: So now you just sit by the computer instead of being in the lab most of the time?

Sven Lidin: Yes, there is some truth in that, although of course what happens is that we can now turn to evermore complex systems. We can always devise a system that is so complicated from the experimental point of view that theorists still are struggling to keep up with us.

Joanna Ross: You challenge them.

Sven Lidin: But on the other hand they keep challenging us. If you look at the physics prize for graphene, for example, now the extraordinary properties of graphene were predicted before by theorists.

This is why the experimentalists tried to make the material because it’s no simple matter to make it. They tried to measure the properties because they knew that there was something interesting in there and they succeeded but it was all thanks to theory that someone even tried.